title: Amyloid-beta42 interacts mainly with insoluble prion protein in the Alzheimer brain.
abstract: The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid-β (Aβ42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for Aβ42 oligomers. Here we report the novel finding that aggregated forms of huPrP and Aβ42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble Aβ from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of Aβ binding sites on huPrP are identified in vitro. One specifically binds to Aβ42 and the other binds to both Aβ42 and Aβ40. Notably, Aβ42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both Aβ40 and Aβ42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble Aβ42 in vivo. Although this work indicated the interaction of Aβ42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/Aβ42 interaction remains to be established.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. wenquan.zou@case.edu
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Zou
authors.forename: Xiangzhu
authors.initials: X
authors.lastname: Xiao
authors.forename: Jue
authors.initials: J
authors.lastname: Yuan
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Puoti
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
authors.forename: Sandy
authors.initials: S
authors.lastname: Richardson
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Zhou
authors.forename: Roger
authors.initials: R
authors.lastname: Zou
authors.forename: Shihao
authors.initials: S
authors.lastname: Li
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
authors.forename: John
authors.initials: J
authors.lastname: McGeehan
authors.forename: Geoff
authors.initials: G
authors.lastname: Kneale
authors.forename: Diego E
authors.initials: DE
authors.lastname: Rincon-Limas
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernandez-Funez
authors.forename: Hyoung-gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Guo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D006801:Humans; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011328:Prions; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)